Neville J. Howard

Effects of Therapy in X-Linked Hypophosphatemic Rickets

BACKGROUND Patients with X-linked hypophosphatemic rickets, which is clinically manifested by growth failure and bowing of the legs, are usually treated with phosphate and a vitamin D preparation. However, the efficacy of this treatment has been disputed, and nephrocalcinosis is a recognized complication of therapy. METHODS We studied 24 patients with X-linked hypophosphatemic rickets (9 boys and 15 girls) ranging in age from 1 to 16 years (median, 5.3). The duration of combination therapy ranged from 0.3 to 11.8 years (median, 3.0). We measured height as a standard-deviation (SD) score (the number of SDs from the mean height for chronologic age). Measurements made before the age of two years or after the onset of puberty were excluded. We compared the results with those reported in 1971 for 16 untreated prepubertal Australian patients. We also determined the severity of nephrocalcinosis (on a scale of 0 to 4, with 0 indicating no abnormalities and 4 stone formation) with renal ultrasonography and whether it could be related to the dosage of phosphate or vitamin D or to other factors. RESULTS Patients treated for at least two years before the onset of puberty (n = 19) had a mean height SD score of -1.08, as compared with -2.05 in the untreated historical controls. The 13 patients who had been treated with calcitriol and phosphate for at least two years had an increase in the mean height SD score of 0.33, from -1.58 to -1.25 (95 percent confidence interval, 0 to 0.67; P = 0.05). Nineteen of the 24 patients (79 percent) had nephrocalcinosis detected on renal ultrasonography. The grade of nephrocalcinosis was significantly correlated with the mean phosphate dose (r = 0.60, P = 0.002), but not with the dose of vitamin D or the duration of therapy. All patients had normal serum creatinine concentrations. CONCLUSIONS Therapy with calcitriol and phosphate may increase the growth of children with X-linked hypophosphatemic rickets. Nephrocalcinosis in these children represents a complication of therapy and is associated with the dose of phosphate received.

Environmental Factors in Childhood IDDM: A population-based, case-control study

OBJECTIVE To identify environmental factors involved in the etiology of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS An estimated 90% of all incident cases of IDDM in patients 0–14 years of age in New South Wales, Australia, were ascertained over 18 months. For each IDDM patient, two age- and sex-matched control subjects were randomly selected from the population. Past environmental exposures were determined with a questionnaire completed by the parents. Response rates were 92% for the IDDM patients (217 of 235) and 55% for the control subjects (258 of 470). The relative risk associated with each exposure was estimated with the odds ratio (OR) adjusted for confounding factors using multiple logistic regression. RESULTS The introduction of cows milk-based infant formula into the diet before 3 months of age was associated with an increased risk (OR 1.52, 95% confidence interval [CI] 1.04–2.24). Exclusive breast-feeding for ≥3 months was associated with a protective effect (OR 0.66, 95% CI 0.45–0.97). High dietary intake of cows milk protein in the 12 months before the onset of diabetic symptoms was also associated with an increased risk (OR 1.84, 95% CI 1.12–3.00). A recent infection (during the 3 months before onset of diabetic symptoms) was more common in the patients than the control subjects (OR 2.92, 95% CI 1.96–4.35), as was day care attendance before the age of 3 (OR 1.73, 95% CI 1.00–3.00). When two age-groups, defined by the median age at onset of diabetes, were compared, the associations with early infant-feeding were stronger among the younger group (<9.2 years), and associations with recent diet and recent infection were stronger among the older group (≥9.2 years). CONCLUSIONS These results indicate an increased risk of IDDM associated with early dietary exposure to cows milk-containing formula, short duration of exclusive breast-feeding, high intake of cows milk protein in the recent diet, recent infection, and early attendance at day care.

Neonatal thyrotoxicosis: Intellectual impairment and craniosynostosis in later years

2. Kelly WF, Joplin GF, and Pearson GW: Go0adotrophin deficiency and adrenocortical insufficiency in children: a new syndrome, Br Med J 2:98, 1977. 3. Golden MP, L!ppe BM, and Kaplan SA: Congenital adrenal hypoplasia and hypogonadotropic hypogonadism, Am J Dis Child 131:1117, 1977. 4. Black S, Brook CG, and Cox PJ: Congenital adrenal hypoplasia and gonadotrophin deficiency, Br Med J 2:996, 1977. 5. Brook CG, Bambach M, Zachmann M, and Prader A: Familial congenital adrenal hypoplasia, Helv Paediatr Acta 28:277, 1973. 6. Tanner JM, Whitehouse RH, and Takaishi M: Standards from birth to maturity for height, weight, height velocity, and weight velocity: British children, 1965, Arch Dis Child 41:454, 1966. 7. lllig R, Pluznik S, Werner H, and Prader A: The effect of synthetic LHRH on plasma LH and FSH in 92 children and adolescents with delayed, disturbed or deficient sexual maturation, Horm Metab Res Suppl Series 5:156, 1974. 8. Zachmann M: The evaluation of testicular endocrine function before and in puberty. Effect of a single dose of human chorionic gonadotropin on urinary steroid excretion under normal and pathological conditions, Acta Endocrinol [Suppl] 164:3, 1972. 9. Prader A, Illig R, and Zachmann M: Prenatal LH-deficiency as possible cause of male pseudohermaphroditism, hypospadias, hypogenitalism and cl;yptorchidism, Pediatr Res 10:883, 1976 (abstr). 10. Ducharme JR, Forest MG, De Peretti E, Semp6 M, Collu R, and Bertrand J: Plasma adrenal and gonadal sex steroids in human pubertal development, J Clin Endocrinol 42:468, 1976.

The Effect of Prepubertal Diabetes Duration on Diabetes: Microvascular Complications in Early and Late Adolescence

OBJECTIVE To define the significance of prepubertal diabetes duration in the development of diabetic microvascular complications in adolescents. RESEARCH DESIGN AND METHODS Study A compares complications in 38 prepubertal (PreP) and 140 pubertal (Pub) subjects of the same age (10-14 years) and diabetes duration (3–12 years) to determine if the absence of puberty itself confers a lower risk of complications. Study B examines the importance of prepubertal and pubertal diabetes duration in 193 older adolescents (ages 15–22 years) with prepubertal onset of diabetes. Retinopathy status was assessed using stereoscopic fundus photography of seven fields per eye. Albumin excretion rate (AER) was assessed by three consecutive overnight urine collections, using a polyclonal radioimmunoassay. RESULTS In study A, there were no significant differences between the PreP and Pub groups for retinopathy (27 vs. 29%, P = 0.8) or differences in elevated AER (17 vs. 31%, P = 0.1). In study B, longer prepubertal diabetes duration improved the prediction for retinopathy over postpubertal duration alone (P < 0.0005). No relationship with duration was found for elevated AER (> 7.5, > 15, and > 30 micrograms/min). CONCLUSIONS Prepubertal subjects with diabetes did not have less retinopathy or elevated albumin excretion compared with pubertal subjects of the same age. Prepubertal diabetes duration is significantly related to the presence of retinopathy in adolescents.

Reduced Frequency of HLA DRB1*03-DQB1*02 in Children with Type 1 Diabetes Associated with Enterovirus RNA

Enteroviruses have been associated with type 1 diabetes mellitus (T1DM), but it is unclear whether there is a distinct disease subtype. Plasma and stool samples from 206 consecutively diagnosed children and 160 healthy control children were analyzed by reverse-transcription polymerase chain reaction for the RNA of 60 enteroviruses. More children with diabetes tested positive for enterovirus RNA (30% vs. 4%; odds ratio, 11.1; 95% confidence interval, 4.7-25.7; P<.001). Enterovirus 71 was detected in 25% of children; these were temporally associated with outbreaks in Southeast Asia and Australia. Fewer children with the diabetes-associated human leukocyte antigen DRB1*03-DQB1*02 genotype tested positive for enterovirus RNA (P=.02). More children presenting with severe diabetic ketoacidosis (pH, <7.1) tested positive for enterovirus RNA (P=.04). These results suggest that there is a subgroup of patients with T1DM, who are at low genetic risk, in whom enteroviruses contribute to diabetes onset.

Prevalence of diabetes complications 6 years after diagnosis in an incident cohort of childhood diabetes

Aims  To examine the prevalence of early diabetes complications 6 years after diagnosis of diabetes. The hypothesis that initial contact with a multidisciplinary team would be associated with a reduced risk of microvascular complications was tested in this cohort.

Autonomic Nerve Testing Predicts the Development of Complications: A 12-year follow-up study

OBJECTIVE—Cardiac autonomic nerve tests have predicted increased mortality in adults with diabetes, predominantly due to nephropathy, cardiac disease, and hypoglycemia. The significance of subclinical autonomic nerve test abnormalities has not been systematically studied in adolescents. We aimed to reassess an adolescent cohort, whose autonomic nervous system had been tested 12 years earlier by both pupillometry and cardiovascular tests. RESEARCH DESIGN AND METHODS—From 1990 to 1993, adolescents with type 1 diabetes (n = 335) were assessed for autonomic neuropathy (median age 14.7 years [interquartile range 13.0–16.8], duration of diabetes 6.3 years [4.0–9.6], and A1C 8.3% [7.5–9.4]). Between 2003 and 2005, contact was made with 59% of the original group. Individual assessment 12 years later included completion of a validated hypoglycemia unawareness questionnaire (n = 123) and urinary albumin-to-creatinine ratio (n = 99) and retinal (n = 102) screening, as well as analysis of reports from external doctors (n = 35). RESULTS—At baseline, there was no difference in age, duration of diabetes, or complications between those who participated in the follow-up phase (n = 137) and those who did not participate (n = 196). However, baseline A1C was lower in the follow-up participants (8.2 vs. 8.5% for participants vs. nonparticipants, respectively, P = 0.031). At 12 years of follow-up, 93% were aware and 7% were unaware that they had hypoglycemia; 32 (31%) had no retinopathy, but 10% required laser therapy, and 80 (81%) had no microalbuminuria. Small pupil size at baseline was independently associated with the development of microalbuminuria (odds ratio 4.36 [95% CI 1.32–14.42], P = 0.016) and retinopathy (4.83 [1.3–17.98], P = 0.019) but not with the development of hypoglycemia unawareness. There was no association with baseline cardiovascular tests and the development of complications 12 years later. CONCLUSIONS—In this study, we found an association between baseline pupillometry tests and the presence of microalbuminuria and retinopathy at 12 years of follow-up. This suggests that pupillometry abnormalities may be early indicators of patients who are at high risk of future microvascular disease.

Combined pituitary hormone deficiency in Australian children: clinical and genetic correlates

objective Mutations in the gene for the POU domain transcription factor POU1F1 (human Pit‐1) have been reported in patients with GH, TSH and PRL deficiencies. PROP1 (Prophet of Pit‐1) gene mutations also cause gonadotrophin deficiencies and in some cases partial ACTH deficiency. This study analyses the POU1F1 and PROP1 genes in a cohort of Australian children with combined pituitary hormone deficiency (CPHD) and correlates results with patient phenotype.

Evaluation of ICA512As in Combination With Other Islet Cell Autoantibodies at the Onset of IDDM

OBJECTIVE The ICA512 pancreatic islet autoantigen is a putative tyrosine phosphatase that is co-identified with the earlier described 40-kDa autoantigen. We report the frequency of autoantibodies to islet cell antigen 512 (ICA512As) in recent-onset IDDM and compare this with other islet cell autoantibodies, including those to GAD (GADAs), insulin (IAAs), and islet cell cytoplasm (ICAs) identified by immunofluorescence. RESEARCH DESIGN AND METHODS Sera from 232 children aged between 9 months and 14.9 years collected within 14 days of diagnosis were tested for ICA512As by a radioimmunoprecipitation assay. The results were compared with previously reported data for GADAs (n = 232), IAAs (n = 167), and ICAs (n = 230). RESULTS The frequency of a positive result for ICA512As in children with newly diagnosed IDDM was 60%. The frequency was greater for children with an age of onset between 5 and 10 years (69%) than for children aged < 5 years (49%) and aged between 10 and 15 years (56%). The frequencies for other autoantibody reactivities were 69% for GADAs, 65% for IAAs, and 70% for ICAs. A combination of positive results for ICA512As, GADAs, and IAAs gave a sensitivity for the diagnosis of childhood IDDM of 95%, which was not significantly increased by a positive result for ICAs (96%). CONCLUSIONS Our results further establish that positivity in a combination of tests is more valuable for the prediction of IDDM than a result for any single autoantibody and that the age of the patient should be considered when selecting the combination of tests to use.

Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10IUml ‐1), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9‐176.1, than in all other children on the database. The incidence in patients with Turners syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10–20 IUml ‐1) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors’practice is now to start GH replacement at less than the usual recommended dose of 14IUm‐2 week‐1 in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilledema does not exclude the diagnosis.